RU2157371C2 - Substituted benzothienylpiperazines, methods of their synthesis, pharmaceutical composition - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to benzothienyl-piperazines of the general formula (I)

where X means hydrogen or halogen atom; Y means -CN or -NR¹R² where p is the whole number 1 or 2; m is the whole number 0, 1 or 2; n is the whole number 2, 3 or 4 except for the case when Y is CN then n can be 1 also; R¹ means hydrogen atom, (C₁-C₆)-alkyl or alkoxycarbonyl; R² means hydrogen atom, (C₁-C₁₀)-alkylcarbonyl, (C₃-C₁₂)-cycloalkylcarbonyl, hydroxy-(C₁-C₆)-alkylcarbonyl, phenyl-carbonyl possibly substituted with halogen atom, trifluoro-methyl-, thienylcarbonyl- or benzothienylcarbonyl-group or R¹ and R² in common with nitrogen atom to that they are bound form the cycle of the formula (II)

where A means C= O or CH₂; B means C=O, CHOH, CH₂ or CH₂CH₂ and Z means hydrogen atom, and their pharmaceutically acceptable additive acid salts under condition that when X is H then n can not be 4 and R¹ and R² both can not be hydrogen atom. Invention proposes also methods of synthesis of indicated compounds and pharmaceutical composition based on thereof. Compounds of the formula (I) and composition based on thereof show antipsychotic activity and can be used for treatment of psychotic patients. EFFECT: improved method of synthesis, valuable medicinal properties of compounds. 15 cl, 2 tbl, 18 ex

Description

 This invention relates to benzothienylpiperazines. More specifically, this invention relates to benzothienylpiperazines having antipsychotic activity and their use as antipsychotic drugs.

 In the relevant technique, therapeutic treatment of schizophrenia patients is known by administering antipsychotic drugs such as chlorpromazine, haloperidol, sulpiride and chemically closely related compounds. Although the symptoms of schizophrenia are successfully regulated, treatment with such drugs is not a way to treat a psychotic patient who will certainly experience a relapse when the drug is withdrawn. Thus, there continues to be a need for the development of drug technology for the treatment of psychosis.

 In addition, some of the known antipsychotics cause unwanted side effects. For example, side effects of many antipsychotic drugs include the so-called extrapyramidal symptoms, such as rigidity and trembling, continuous agitated gait and distant dyskinesia, which causes grimaces, involuntary movements of the face and limbs. Orthostatic hypotension is also common. Thus, there is also a need to develop antipsychotic drugs that cause less or more severe manifestation of these common side effects.

в которой X представляет водород, галоген, гидрокси, (C₁-C₆)-алкокси, амино или трифторметил, и
Y - обозначает -CN или -NR¹R²,
где l обозначает целое число 1 или 2,
m обозначает целое число, равное 0, 1 или 2,
n обозначает целое число, равное 2, 3 или 4, за исключением случая, когда Y - CN, то n может быть равно также 1,
R¹ обозначает водород, (C₁-C₆)алкил или (C₁-C₆)-алкилкарбонил,
R² обозначает водород, (C₁-C₁₀)алкилкарбонил, (C₃-C₁₂циклоалкилкарбонил, гидрокси-(C₁-C₆)алкилкарбонил, фенилкарбонил, тиенилкарбонил или бензотиенилкарбонил, или
R¹ и R² вместе с атомом азота, с которым они связаны, образуют цикл:

где A обозначает C=O или CH₂, и
B обозначает C=O, CHOH, CH₂ или CH₂CH₂, и
Z обозначает водород, гидрокси, (C₁-C₆)-алкокси, амино или трифторо, и их фармацевтически приемлемые соли кислотного присоединения, их фармацевтические композиции и их применение для лечения психозов.The present invention helps to meet these drug development needs by providing compounds of the formula:

in which X represents hydrogen, halogen, hydroxy, (C ₁ -C ₆ ) -alkoxy, amino or trifluoromethyl, and
Y - is —CN or —NR ¹ R ² ,
where l is an integer 1 or 2,
m denotes an integer equal to 0, 1 or 2,
n denotes an integer equal to 2, 3 or 4, except when Y is CN, then n may also be 1,
R ¹ is hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkylcarbonyl,
R ² is hydrogen, (C ₁ -C ₁₀ ) alkylcarbonyl, (C ₃ -C ₁₂ cycloalkylcarbonyl, hydroxy- (C ₁ -C ₆ ) alkylcarbonyl, phenylcarbonyl, thienylcarbonyl or benzothienylcarbonyl, or
R ¹ and R ² together with the nitrogen atom to which they are attached form a cycle:

where A denotes C = O or CH ₂ , and
B is C = O, CHOH, CH ₂ or CH ₂ CH ₂ , and
Z is hydrogen, hydroxy, (C ₁ -C ₆ ) alkoxy, amino or trifluoro, and their pharmaceutically acceptable acid addition salts, their pharmaceutical compositions and their use for the treatment of psychoses.

 The present invention provides a pharmaceutical composition which comprises a compound of the invention and a pharmaceutically acceptable carrier. In one embodiment of the invention, the pharmaceutical composition is an antipsychotic composition comprising a compound of the invention in an amount sufficient to cause an antipsychotic effect.

 In addition, the present invention provides a method of treating psychoses, which comprises administering to a patient a pharmaceutically effective amount of a compound of the invention.

 The compounds of this invention may contain a wide variety of substituents and chemical groups.

 The term “alkyl,” as used herein, means a straight or branched hydrocarbon group containing no unsaturated bonds, such as, for example, methyl, ethyl, isopropyl, propyl, 2-butyl, t-butyl, neopentyl or hexyl.

 The term “cycloalkyl,” as used herein, refers to a monocyclic or bicyclic hydrocarbon ring, such as, for example, cyclopropyl, cyclohexyl or adamantyl.

 The term “alkoxy” as used herein means a monovalent substituent comprising an alkyl group bound via ether oxygen having a free valence bond on oxygen, such as, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy or hexyloxy.

 The term “alkylcarbonyl” as used herein refers to a monovalent substituent comprising an alkyl group linked via a carbonyl group having a free valence bond on a carbonyl group, such as, for example, acetyl, propionyl or isopropylcarbonyl.

The term “phenyl” as used herein refers to unsubstituted phenyl or phenyl substituted with 1, 2 or 3 substituents consisting of halogen, trifluoromethyl, phenyl and (C ₁ -C ₆ ) alkyl, such as, for example, 4-fluorophenyl or 2- (4- (trifluoromethyl) phenyl) phenyl.

The term “thienyl,” as used herein, refers to unsubstituted thiophene or thiophene substituted with 1 or 2 substituents selected from: halogen, alkoxy, and (C ₁ -C ₆ ) alkyl.

The term “benzothienyl,” as used herein, refers to unsubstituted benzothiophene or benzothiophene substituted with 1, 2, or 3 substituents on the benz ring consisting of halogen, trifluoromethyl, alkoxy, and (C ₁ -C ₆ ) -alkyl.

 Unless otherwise indicated, the term “halogen,” as used herein, means fluoro, chloro, iodo and bromo.

 Throughout the description and within the attached paragraphs, this chemical formula or name includes all geometric, optical, and stereoisomers when they exist.

в которой X обозначает водород или галоген, и
Y обозначает -CH или -NR¹R²,
где m - целое число от 0 до 2,
n - целое число, равное 2, 3 или 4,
R¹ - водород, (C₁-C₆)алкилкарбонил,
R² - водород, (C₁-C₁₀)алкилкарбонил, (C₃-C₁₂)-циклоалкилкарбонил, гидрокси-(C₁-C₆)алкилкарбонил, фенилкарбонил, тиенилкарбонил или бензотиенилкарбонил, или
R¹ и R² вместе с азотом, с которым они связаны, образуют цикл:

где A обозначает C=O или CH₂, и
B обозначает C=O, CHOH, CH₂, CH₂CH₂, и
его фармацевтически приемлемые соли кислотного присоединения.More specifically, this invention relates to a compound of the formula:

in which X represents hydrogen or halogen, and
Y is —CH or —NR ¹ R ² ,
where m is an integer from 0 to 2,
n is an integer equal to 2, 3 or 4,
R ¹ is hydrogen, (C ₁ -C ₆ ) alkylcarbonyl,
R ² is hydrogen, (C ₁ -C ₁₀ ) alkylcarbonyl, (C ₃ -C ₁₂ ) -cycloalkylcarbonyl, hydroxy- (C ₁ -C ₆ ) alkylcarbonyl, phenylcarbonyl, thienylcarbonyl or benzothienylcarbonyl, or
R ¹ and R ² together with the nitrogen with which they are bound form a cycle:

where A denotes C = O or CH ₂ , and
B is C = O, CHOH, CH ₂ , CH ₂ CH ₂ , and
its pharmaceutically acceptable acid addition salts.

в которой X - водород или галоген,
m равно 0 или 2,
n равно 2, 3 или 4,
R¹ обозначает водород или (C₁-C₆)алкилкарбонил, и
R² обозначает водород, (C₁-C₁₀)алкилкарбонил, (C₃-C₁₂)циклоалкилкарбонил, гидрокси(C₁-C₆)-алкилкарбонил, тиенилкарбонил или бензотиенилкарбонил и фармацевтически приемлемые соли кислотного присоединения.One of the preferred embodiments of the invention are compounds of the formula:

in which X is hydrogen or halogen,
m is 0 or 2,
n is 2, 3 or 4,
R ¹ is hydrogen or (C ₁ -C ₆ ) alkylcarbonyl, and
R ² is hydrogen, (C ₁ -C ₁₀ ) alkylcarbonyl, (C ₃ -C ₁₂ ) cycloalkylcarbonyl, hydroxy (C ₁ -C ₆ ) alkylcarbonyl, thienylcarbonyl or benzothienylcarbonyl and pharmaceutically acceptable acid addition salts.

In this embodiment, it is preferable:
X is halogen
m is 0, and
n is 4.

Most desirable
X is 6-F,
R ¹ is hydrogen or acetyl, and
R ² is hydrogen, isopropylcarbonyl, adamantylcarbonyl, 4-fluorophenylcarbonyl, 2-thienylcarbonyl, 2-benzothienylcarbonyl, 2-hydroxy-2-methyl-ethylcarbonyl or 2- / 4 '- (trifluoromethyl) -1,1'-biphenyl /.

где X обозначает водород или галоген,
m равно 0 или 2,
n равно 2, 3 или 4,
A обозначает C=O или CH₂,
B обозначает C=O, CHOH, CH₂ или CH₂CH₂, и их фармацевтически приемлемые соли кислотного присоединения.Another preferred embodiment of the invention are compounds of the formula:

where X is hydrogen or halogen,
m is 0 or 2,
n is 2, 3 or 4,
A is C = O or CH ₂ ,
B is C = O, CHOH, CH ₂ or CH ₂ CH ₂ , and their pharmaceutically acceptable acid addition salts.

In this embodiment, preferably
X is halogen,
m is 0, and
n is 4.

In this embodiment, most preferably
X is 6-F,
m is 0,
n is 4
A is C = O or CH ₂ , and
B is C = O, CHOH, CH ₂ CH ₂ or CH ₂ .

The compounds of this invention are prepared by the following method. Unless otherwise specified, the substituents R ¹ , R ² , A, B, X, Y and Z and the integers l, m and n are as defined above.

 The compounds of this invention are prepared by the initial reaction of a suitably substituted 1- (benzo [b] thien-3-yl) piperazine (A) with a suitable haloalkylphthalimide (B) to give a compound of formula II.

Реакцию обычно проводят в подходящем растворителе, таком как ацетонитрил или диметилформамид (DMF) в присутствии кислотного акцептора, такого как, например, карбамат калия или карбонат натрия, и небольшого количества иодида калия или иодида натрия при температурах приблизительно от 20^oC до 100^oC, предпочтительно примерно от 25^oC до 90^oC, наиболее желательно, приблизительно, от 75 до 85^oC.

The reaction is usually carried out in a suitable solvent, such as acetonitrile or dimethylformamide (DMF) in the presence of an acid acceptor, such as, for example, potassium carbamate or sodium carbonate, and a small amount of potassium iodide or sodium iodide at temperatures from about 20 ^o C to 100 ^o C preferably from about 25 ^° C. to about 90 ^° C., most preferably from about 75 ^° C. to about 85 ^° C.

 Compound II is reduced with a suitable reducing agent such as lithium aluminum hydride to give isoindoles of the formula III.

Реакцию обычно проводят в апротонном органическом растворителе, таком как тетрагидрофуран (THF) при температуре приблизительно от 25^oC до 75^oC, предпочтительно, около 50^oC.

The reaction is usually carried out in an aprotic organic solvent such as tetrahydrofuran (THF) at a temperature of from about 25 ^° C. to about 75 ^° C., preferably about 50 ^° C.

Alternatively, the reduction is carried out with sodium borohydride in a protic solvent such as methanol or ethanol, or a mixture of alkanols and other organic solvents such as dichloromethane or chloroform at a temperature of from about 0 ^° C to 80 ^° C, preferably about 50 ^° C , which leads to hydroxylactam of the formula IV.

Соединение формулы IV затем восстанавливают, используя триалкилсилан, такой как триэтилсилан, и органическую карбоновую кислоту, такую как трифторуксусная кислота, получая лактам формулы V.

The compound of formula IV is then reduced using trialkylsilane, such as triethylsilane, and an organic carboxylic acid, such as trifluoroacetic acid, to give lactams of the formula V.

Обычно, реакцию проводят в органическом растворителе, таком как дихлорметан, при температуре приблизительно от 0^oC до 25^oC.

Typically, the reaction is carried out in an organic solvent, such as dichloromethane, at a temperature of from about 0 ^° C. to about 25 ^° C.

 Alternatively, the compound of formula II can be successfully treated with sodium borohydride and acetic acid to give the primary amine of formula VII.

Реакцию обычно выполняют в спирте и воде, предпочтительно, 6:1 изопропанол/вода, при температуре приблизительно от 20^oC до 80^oC.

The reaction is usually carried out in alcohol and water, preferably 6: 1 isopropanol / water, at a temperature of from about 20 ^° C. to about 80 ^° C.

в которой R² - как определено выше.A compound of formula VII is reacted with an organic acid chloride to give a compound of formula VIII

in which R ² as defined above.

The reaction is usually carried out in an aprotic organic solvent, such as dichloromethane, in the presence of an acid acceptor, such as a tertiary amine, for example triethylamine, at a temperature of from about 0 ^° C to 30 ^° C, preferably about 20 ^° C.

The compound of formula VIII is then acylated with another organic acid chloride under the conditions described above to give a compound of formula I in which R ^{1 is} not hydrogen.

Сульфоксиды и сульфонаты изобретения получают из соединений формулы I, в которой m = 0, или посредством известных в технике способов, например, как описано в US-A-5.240.927.

The sulfoxides and sulfonates of the invention are prepared from compounds of formula I in which m = 0, or by methods known in the art, for example, as described in US-A-5.240.927.

 The starting compounds of formula A are known in the art, for example, preparation methods and literature references included in US-A-5.240.927 and the references cited here.

 The compounds of this invention are useful in the treatment of psychoses due to their ability to induce an antipsychotic response in mammals. Antipsychotic activity is determined by testing on excited (climbing) mice according to a procedure similar to that described by P. Protais et al., Psychopharmacol., 50: 1 (1976) and B. Costall, Eur. Y. Pharmacol., 50:39 (1978).

 The male mice (23-27 g) used for CK-1 trials undergo group rehabilitation under standard laboratory conditions. Mice are separately housed in cages made of metal rods (4 "x 10") and given one hour to adapt and get used to the new environment. Then, apomorphine is administered subcutaneously in an amount of 1.5 mg / kg, a dose that causes excitation (climbing) in all test mice after 30 minutes. Compounds tested for antipsychotic activity are injected intraperitoneally or given as oral dosages at various time intervals, for example 30 minutes, 60 minutes, etc. before infection with apomorphine at a protective dose of 10-60 mg / kg.

To evaluate the excitation, 3 readings are taken, obtained at 10, 20 and 30 minutes after administration of apomorphine, respectively, on the following scale:
Excited behavior of mice (climbing):
(no climbing)
4 paws on the bottom (not excited) - indicator 0
2 paws on the floor (rise on hind legs) - indicator 1
4 paws on the wall (full climbing) - indicator 2
Spontaneous climbing of mice is discarded before apomorphine injection.

 Animals with climbing completely dependent on apomorphine hang on the cell walls rather motionless for a long period of time. In contrast, climbing only under the influence of simple motor stimulation usually lasts only a few seconds.

Climbing indices are calculated individually (maximum indicator: 6 per mouse according to 3 indications) and the total indicator of the control group (solvent intraperitoneal apomorphine subcutaneously) is taken as 100%. The percentage response at a dose of 20 mg / kg or ED ₅₀ values with a 95% degree of reliability calculated by linear regression analysis for some compounds of this invention, as well as for standard antipsychotic agents, are presented in table 1.

 An antipsychotic reaction is achieved when the compounds of this invention are administered to a patient in need of such treatment in the form of an effective oral, parenteral or intravenous dose of 0.01 to 50 mg / kg body weight per day. However, it is clear that for any particular patient, specific dosage regimens designed according to individual need and a professional assessment of personal administration or monitoring the administration of the above compound are required. It should also be understood that the dosages given above are only examples and do not limit to any extent the scope or application of this invention. Effective amounts of the compounds of this invention can be administered to a patient by any of the usual methods, for example, orally, in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions.

 The compounds of this invention, although effective per se, can be formulated and administered in the form of their pharmaceutically acceptable acid addition salts for stability, crystallization, increased solubility and the like. Preferred pharmaceutically acceptable addition salts include salts of mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid, and the like, as well as organic acids, such as salts of dibasic carboxylic acids, for example, maleic acid, fumaric acid, and salts of tribasic carboxylic acids such as carboxy succinic acid, citric acid and the like.

 Effective amounts of the compounds of this invention can be administered orally, for example, with an inert solvent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the compounds of the invention can be combined with an excipient and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, cachets, chewing gums and the like. These preparations must contain at least 0.5% of the active compounds of the invention.

 Tablets, pills, capsules, cachets, and the like may also contain the following ingredients: binders such as microcrystalline cellulose, gum tragacanth or gelatin, an excipient such as starch or lactose, a disintegrant such as alginic acid. Primogel, corn starch, and the like: a lubricant such as magnesium stearate or Sterotes, glidants such as colloidal silicon dioxide, and sweeteners such as sucrose or saccharin, or a flavoring agent such as peppermint, methyl salicylate, or orange corrigent. When the dosage is in the form of a capsule, it may contain, in addition to the above types of substances, a liquid carrier, such as a fatty oil. Other dosage unit forms may contain a variety of substances that modify the physical form of the dosage unit, for example, such as coatings. Thus, tablets or pills may be coated with sugar, gelatin or other enteric-coating substances. A syrup may contain, in addition to the active compounds, sucrose as a sweetener and some preservatives, colorants and flavoring agents. The materials used in the preparation of these various compositions should be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administration, the active compounds of this invention may be included in a solution or suspension. These preparations must contain at least 0.1% active compound, but their content can vary from about 0.5 to 50% by weight. The amount of active compounds in such compositions is the amount required to obtain a suitable dose. Preferred compositions and preparations according to this invention are prepared so that the standard parenteral dose contains from 0.5 to 100 mg of the active compound.

 Solutions and suspensions may also include the following components: a sterile solvent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycols or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl parabens, antioxidants such as ascorbic acid or bisulfite: complexones, such as ethylenediaminetetraacetic acid, buffers, such as acetates, citrates or phosphates, and tonics, such as sodium chloride s or dextrose. The parenteral preparation may be in ampoules, disposable syringes or multiple dose vials of glass or plastic.

The following examples are illustrative and are not limiting of the invention. Unless otherwise specified, all temperatures are given in degrees Celsius ( ^o C).

Example 1
6-Chloro-3-piperazinylbenzo [b] thiophene-1,1-dioxide
A mixture of 3,6-dichlorobenzo [b] thiophene-1,1-dioxide (16.00 g, 0.0681 mol), piperazine (20.52 g, 0.238 mol) and dichloromethane (300 ml) is heated at reflux a refrigerator. After 1 hour, TLC analysis showed that dichlorosulfone was used up (Rf = 0.47, 30% ethyl acetate in hexane, silica gel). The turbid mixture is washed with 0.25 N. NaOH (400 ml), H ₂ O (300 ml), brine (250 ml), dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 50% methanol in dichloromethane, to give 12.90 g (66.5%) of a yellow solid. A 1.6 g sample was recrystallized from dichloromethane / diethyl ether to give 0.480 g of pale yellow crystals: mp. 154 ^o C decom.

Analysis
Calculated for C ₁₂ H ₁₃ ClN ₂ O ₂ : 50.61% C 4.60% H 9.84% N
Found: 50.43% C 4.59% H 9.73% N
Example 2
N- [2- [4- (6-Fluorobenzo [b] thien-3-yl) -1-piperazinyl] ethyl] phthalimide
A mixture of N- (2-bromoethyl) phthalimide (8.5 g, 33.55 mmol), (6-fluorobenzo [b] thien-3-yl) -1-piperazine (6.6 g, 27.96 mmol), K ₂ CO ₃ (7.7 g, 55.8 mmol) and NaI (10 mg) in 150 ml of dry CH ₃ CN are heated at 85 ^° C. with stirring under N ₂ . After 18 hours, the mixture was cooled to room temperature, diluted with water and partitioned between EtOAc / H ₂ O. The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The remaining solid orange product is chromatographed on silica gel using a 2: 1 heptane: EtOAc eluent to give 11.30 g of a crude product, (25.18 mmol, 90.07%) homogeneous by TLC (silica, 1: 1 heptane: EtOAc, Rf = 0.20). This crude product was recrystallized from a heptane: EtOAc mixture to give a primary product of 3.92 g (9.58 mmol, 34.38%) as a white solid, mp. 147-149 homogeneous by TLC.

Analysis:
Calculated for C ₂₂ H ₂₀ FN ₃ O ₂ S: 64.53% C 4.92% H 10.26% N
Found: 64.39% C 4.77% H 10.25% N
Example 3
2- [2- [4- (6-Fluorobenzo [b] thien-3-yl) -1-piperazinyl] ethyl] -2,3-dihydro-3-hydroxy-1H-isoindol-1-one
To a stirred suspension of N- [2- [4- (6-fluorobenzo [b] thien-3-yl) -1-piperazinyl] ethyl] phthalimide (2.7 g, 6.6 mmol) in a mixture of 200 ml of absolute EtOH and 50 ml of CH ₂ Cl ₂ in an atmosphere of N ₂ add sodium borohydride (0.56 g, 14.8 mmol) per serving. The mixture is stirred at room temperature for 15 minutes, during which time the solid product dissolves. At the end of 15 minutes, TLC silica, 1: 1 heptane: EtOAc shows the absence of residual starting material and a main spot with a lower Rf appears.

The solution was concentrated in vacuo to a solid state, and this product was filtered through a pad of silica gel using EtOAc eluent. The filtrate was concentrated to a yellowish solid. This crude product was triturated with EtOAc and the resulting solid product was collected and dried in vacuo. This provides an initial collection of pure product of 1.56 g (3.79 mmol, 57.50%), T. pl. 188-190 ^o .

Analysis:
Calculated for C ₂₂ H ₂₂ FN ₃ O ₂ S: 64.21% C 5.39% H 10.21% N
Found 63.95% C 5.19% H 10.03% N
Example 4
2- [4- [4- (6-Fluorobenzo [b] thien-3-yl) -1-piperazinyl] butyl] -1H-isoindole-1,3 (2H) -dione
A mixture of 1- (6-fluorobenzo [b] thien-3-yl) piperazine (20.0 g, 84.6 mmol), N- (4-bromobutyl) phthalimide (26.3 g, 93.2 mmol), anhydrous potassium carbonate (17.5 g, 127 mmol), KI (1.40 g, 8.43 mmol) and anhydrous acetonitrile (500 ml) were stirred by heating under reflux for 17 hours. The thick suspension was filtered, the insoluble product was washed with chloroform (2 x 100 ml), and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform (400 ml), washed with water (200 ml) and dried (MgSO ₄ ). The solvent was removed in vacuo and the product was chromatographed on silica gel with 20% heptane / ethyl acetate as the eluent to give 25.8 g of a yellow solid. Recrystallization from diethyl ether afforded 10.9 g (29%) of the title compound as a yellow powder: mp. = 94-95 ^o C.

Analysis:
Calculated for C ₂₄ H ₂₄ FN ₃ O ₂ S: 65.88% C 5.53% H 9.60% N
Found: 65.82% C 5.80% H 9.54% N
Example 5
4- (6-Fluorobenzo [b] thien-3-yl) -1-piperazinbutanamine (Z) -2-butenedioate (1: 2)
To a stirred mixture of 2- [4- [4- (6-fluorobenzo [b] thien-3-yl) -1-piperazinyl] butyl] -1H-isoindole-1,3 (2H) -dione (14.5 g, 33, 1 mmol) and 6: 1 isopropanol / water (170 ml) at room temperature under nitrogen atmosphere add sodium borohydride (6.28 g, 166 mmol). After 25 hours, acetic acid (35.7 g, 594 mmol) was carefully added. After stirring the mixture for 0.5 hours at room temperature, the reaction mixture was heated at 80 ^° C. for 3 hours. The reaction mixture was concentrated in vacuo to a yellow residue, which was dissolved in water (300 ml) and extracted with diethyl ether (150 ml). The aqueous layer was cooled to 0 ^° C., the solution was made alkaline by adding 50% aqueous NaOH to pH 12, and extracted with dichloromethane (2 x 125 ml). The combined extracts were washed with water (100 ml), dried (K ₂ CO ₃ ) and concentrated in vacuo to give 9.60 g of a viscous solid. Maleic acid (7.00 g, 60.3 mmol) is added to a solution of the crude free base (9.28 g, 30.2 mmol) in ethanol (300 ml) and the mixture is heated until a solution is obtained. The solvent was removed in vacuo to give a crude salt of an orange-brown solid. After two recrystallizations from ethanol, 9.82 g (55%) of the title compound are obtained as an off-white powder, mp. = 151-153 ^o C.

Analysis:
Calculated for C ₁₆ H ₂₂ FN ₃ S • C ₈ H ₈ O ₈ : 53.42% C 5.60% H 7.79% N
Found: 53.72% C 5.82% H 7.74% N
Example 6
N- [4- [4- (6-Fluorobenzo [b] thien-3-yl) -1-piperazinyl] butyl] acetamide
To a 0 ^° C solution of 4- (6-fluorobenzo [b] thien-3-yl) -1-piperazine butanamide (3.13 g, 10.2 mmol), triethylamine (1.45 g, 14.3 mmol) and dichloromethane (60 ml) under nitrogen atmosphere, acetyl chloride (0.883 g, 11.3 mmol) is added rapidly. The reaction mixture was stirred at 0 ^° C. for 2 hours and then further at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (140 ml), washed with 5% aqueous NaOH (100 ml) and dried (K ₂ CO ₃ ). The solvent was removed in vacuo to give a brown solid. The crude product is chromatographed on silica gel with 10% methanol / dichloromethane eluent to give a tan solid. Recrystallization from ethyl acetate gave 1.85 g (52%) of the title compound as beige crystals: mp. = 141-142 ^o C.

Analysis:
Calculated for C ₁₈ H ₂₄ FN ₃ OS: 61.86% C 6.92% H 12.02% N
Found: 61.82% C 7.01% H 11.95% N
Example 7
N-Acetyl-N- [4- [4- (6-fluorobenzo [b] thien-3-yl) -1-piperazinyl] butyl] -2-methyl-propanamide
A solution of isobutyryl chloride (2.34 g, 21.9 mmol) in dry dichloromethane (8 ml) was added over 2 minutes to a solution of N- [4- [4- (6-fluorobenzo [b] thien-3-yl) -1 Piperazinyl] butyl] acetamide (2.51 g, 7.18 mmol), triethylamine (2.18 g, 21.5 mmol), 4-dimethylaminopyridine (0.877 g, 7.18 mmol) and dry dichloromethane (50 ml) at room temperature in a nitrogen atmosphere. After 2.5 hours, the reaction solution was diluted with dichloromethane (100 ml), washed with water (75 ml), dried over MgSO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel using 5% methanol / dichloromethane as the eluent to give 2.91 g of an amber solid.

Recrystallization from tert-butyl methyl ether / heptane afforded 1.52 g (50%) of the title compound as tan crystals: mp. = 98-99 ^o C.

Analysis:
Calculated for C ₂₂ H ₃₀ FN ₃ O ₂ S: 62.98% C 7.21% H 10.02% N
Found: 63.20% C 7.47% H 10.05% N
Example 8
N- [4- [4- (6-fluorobenzo [b] thien-3-yl) -1-piperazinyl] butyl] -2-methyl-propanamide
To a 0 ^o C solution of 4- (6-fluorobenzo [b] thien-3-yl) -1-piperazine-butanamide (4.04 g, 13.1 mmol), triethylamine (1.89 g, 18.6 mmol) and dichloromethane (50 ml) under nitrogen atmosphere, isobutyryl chloride (1.63 g, 15.3 mmol) was added over 6 minutes. The reaction mixture was stirred at 0 ^° C. for 4 hours and then diluted with dichloromethane (140 ml). The mixture was washed successively with 5% aqueous NaOH (100 ml) and water (100 ml), dried (K ₂ CO ₃ ) and concentrated in vacuo to give an off-white solid. The crude product is purified by chromatography on silica gel using 10% methanol / dichloromethane as the eluent to give an off-white solid. Recrystallization from acetate / heptane gave 2.17 g (43%) of the title compound as beige needle crystals: mp. 130-131 ^o C. TLC (silica gel, 10% methanol / dichloromethane) Rf = 0.37. IR (CHCl ₃ ), ¹ H NMR (CDCl ₃ , 200 MHz) and MS (M ⁺ 377, EI, 70 eV) confirm the proposed structure.

Analysis:
Calculated for C ₂₀ H ₂₈ FN ₃ OS: 63.63% C 7.48% H 11.13% N
Found: 63.65% C 7.59% H 11.00% N
Example 9
1- (6-Chlorobenzo [b] thien-3-yl) piperazine
To a solution of 6-chloro-3-piperazinyl-benzo [b] thiophene-1,1-dioxane (6.0 g) and tetrahydrofuran (THF) (30 ml) in a nitrogen atmosphere was added a solution of DIBAl-H (diisobutylaluminum hydride) (0.084 mol ) in toluene (84 ml) dropwise upon cooling with an ice bath. The reaction mixture was stirred at 0 ^° C. for 2 hours, then overnight at room temperature. To the yellow solution, water (5 ml) is added with vigorous stirring at such a rate as to control the evolution of hydrogen. Then add with vigorous stirring 5 N. NaOH (5 ml). The resulting precipitate was filtered and washed with dichloromethane and diethyl ether. The filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (150 ml), washed with water (75 ml) and brine (100 ml), dried over sodium sulfate and concentrated in vacuo to give 5.93 g of a viscous gum which was triturated with diethyl ether. The diethyl ether fraction was concentrated in vacuo to give 2.75 g of a residue which was chromatographed (silica gel, 50% MeOH / CH ₂ Cl ₂ ) to obtain 1.53 g of the product as a clear oil.

Example 10
N- [4- [4- (6-Fluorobenzo [b] thien-3-yl) -1-piperazinyl] butyl] -4-fluorobenzamide
To a 0 ^o solution of 4- (6-fluorobenzo [b] thien-3-yl) -1-piperazine-butanamine (2.45 g, 7.97 mol), triethylamine (1.23 g, 12.2 mmol) and dichloromethane (30 ml) under nitrogen atmosphere add 4-fluorobenzoyl chloride (1.61 g, 10.2 mmol) per serving. The reaction mixture was stirred at 0 ^° C. for 70 minutes and then at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (50 ml) and the mixture was washed successively with 5% aqueous NaOH (50 ml) and water (50 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo to a tan solid. The crude product is chromatographed on silica gel with 10% ethanol / dichloromethane as the eluent, to give 2.22 g of an off-white solid. Recrystallization from ethyl acetate / heptane gave 1.60 g (46%) of the title compound as beige needle crystals. Mp 161-163 ^o C.

Analysis:
Calculated for C ₂₃ H ₂₅ F ₂ N ₃ OS: 64.32% C 5.87% H 9.78% N
Found: 64.15% C 5.68% H 9.50% N
Example 11
4- (6-fluorobenzo [b] thien-3-yl) -1- [4- (isoindol-2-yl) butyl] piperazine
To a stirred suspension of LiAlH ₄ (1.50 g, 37.9 mmol) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere at room temperature is added dropwise a solution of 2- [4- [4- (6-fluorobenzo [b] thien- 3-yl) -1-piperazinyl] butyl] -1H-isoindole-1,3 (2H) -dione (5.95 g, 13.6 mmol) in anhydrous tetrahydrofuran (125 ml) for 20 minutes. After addition, the reaction mixture was stirred at 50 ^° C. for 4 hours and then cooled to room temperature. The reaction mixture is treated sequentially with water (1.5 ml), 15% NaOH (1.5 ml) and water (4.5 ml) and stirred at room temperature for 0.5 hours. The mixture was filtered, insoluble products washed with CHCl ₃ (2 x 50 ml), and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform (200 ml), washed with water (100 ml), dried (K ₂ CO ₃ ) and the solvent was removed in vacuo. The crude product is chromatographed on silica gel with 10% methanol in dichloromethane as the eluent to give 3.5 g of a tan solid. The solid was recrystallized twice from ethyl acetate to give 1.48 g (26%) of the title compound as amber crystals, mp. 118-120 ^o C.

Analysis:
Calculated for C ₂₄ H ₂₈ FN ₃ S: 70.38% C 6.89% H 10.26% N
Found: 70.52% C 7.04% H 10.18% N
Example 12
N- [4- [4- (6-Fluorobenzo [b] thien-3-yl) -1-piperazinyl] butyl] adamantane-1-carboxamide maleate
To a 0 ^o C solution of 4- (6-fluorobenzo [b] thien-3-yl) -1-piperazine-butanamine (2.50 g, 8.13 mmol), triethylamine (1.23 g, 12.2 mmol) and dichloromethane (50 ml) in a nitrogen atmosphere add a solution of 1-adamantanecarbonyl chloride (2.00 g, 10.1 mmol) in dichloromethane (25 ml) quickly. The reaction mixture was stirred at 0 ^° C. for 45 minutes and then 18 hours at room temperature. The reaction solution was diluted with dichloromethane (75 ml) and washed successively with 5% aqueous NaOH (75 ml) and water (75 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product is chromatographed on silica gel with a 2-10% methanol / dichloromethane mixture as eluent to give 2.86 g of an off-white solid. To a solution of the free base (2.66 g, 5.66 mmol) in ethanol (60 ml), maleic acid (0.690 g, 5.94 mmol) is added, the mixture is heated until a solution is obtained and the salt is allowed to crystallize at room temperature. The salt was collected and recrystallized from methanol / ethyl acetate to give 1.93 g (38%) of the title compound as an off-white powder, mp. 200-201 ^o C (decomp.).

Analysis:
Calculated for C ₂₇ H ₃₆ FN ₃ OS • C ₄ H ₄ O ₄ : 63.57% C 6.88% H 7.17% N
Found: 63.36% C 7.02% H 7.12% N
Example 13
N- [4- [4- (6-Fluorobenzo [b] thien-3-yl) -1-piperazinyl] butyl] -2-thiophenecarboxamide (Z) -2-butenedioate (1: 1)
To a 0 ^o C solution of 4- (6-fluorobenzo [b] thien-3-yl) -1-piperazine-butanamine (2.50 g, 8.13 mmol), triethylamine (1.23 g, 12.2 mmol) and dichloromethane (150 ml) in a nitrogen atmosphere add 2-thiophenecarbonyl chloride (1.37 g, 9.34 mmol) per serving. The reaction mixture was stirred at 0 ^° C. for 10 minutes and then at room temperature for 17 hours. The reaction mixture was washed successively with 5% aqueous NaOH (75 ml) and water (75 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product is chromatographed on silica gel, 3-12% ethanol in chloroform as the eluent, to give 2.66 g of a solid product. To a solution of the free base (2.50 g, 5.99 mmol) in ethanol (25 ml), maleic acid (0.730 g, 6.29 mmol) is added, the mixture is heated until a solution is obtained and the solvent is removed in vacuo. The salt was recrystallized from methanol / ethyl acetate to give 2.35 g (54%) of the title compound as an off-white powder. Mp 123-126 ^o C.

Analysis:
Calculated for C ₂₁ H ₂₄ FN ₃ OS ₂ • C ₄ H ₄ O ₄ : 56.27% C 5.29% H 7.87% N
Found: 56.06% C 5.48% H 7.81% N
Example 14
4- (6-Fluorobenzo [b] thien-3-yl) -1-piperazinebutannitrile (Z) -2-butenedioate (1: 1)
A mixture of 1- (6-fluorobenzo [b] thien-3-yl) piperazine (25.0 g, 0.106 mol), 4-bromobutonitrile (18.8 g, 0.127 mmol), anhydrous potassium carbonate (21.9 g, 0.158 mol) and anhydrous acetonitrile (250 ml), stirred while heating to boiling temperature under reflux for 5.5 hours. The thick suspension was filtered, the insoluble products were washed with dichloromethane (2 x 50 ml) and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (300 ml), washed successively with 5% aqueous NaOH (150 ml) and water (150 ml) and dried (Na ₂ SO ₄ ). The solvent was removed in vacuo and the crude product was chromatographed on silica gel with ethyl acetate as the eluent to give 24.3 g (75%) of a yellow solid.

Maleic acid (815 mg, 7.02 mmol) was added to a solution of the free base (2.03 g, 6.69 mmol) in ethanol, and the resulting mixture was heated to obtain a solution. After removing the solvent in vacuo, the resulting salt was recrystallized from ethanol to obtain 2.30 g of the title compound as off-white plates, mp. 163-165 ^o C.

Analysis:
Calculated for C ₁₆ H ₁₈ FN ₃ S • C ₄ H ₄ O ₄ : 57.27% C 5.29% H 10.02% N
Found: 57.27% C 5.19% H 9.98% N
Example 15
4- (6-Fluorobenzo [b] thien-3-yl) -1- [4- (isoindol-2-yl) butyl] piperazine (Z) -2-butenedioate (1: 2)
To a 63 ^° C. solution of 4- (6-fluorobenzo [b] thien-3-yl) -1- [4- (isoindole-2-yl) butyl] piperazine (1.09 g, 2.66 mmol) in ethanol ( 40 ml) maleic acid (0.633 g, 5.45 mmol) is added and the resulting solution is concentrated in vacuo to a dark foam. Rubbing the ethanol / ethyl acetate foam gives a gray powder. The salt was treated with clarifying activated carbon and recrystallized from ethanol to give 1.08 g (63%) of the title compound as a gray powder. Mp 153-155 ^o C.

Analysis:
Calculated for C ₂₄ H ₂₈ FN ₃ S • 2C ₄ H ₄ O ₄ : 59.89% C 5.65% H 6.55% N
Found: 59.80% C 5.74% H 6.53% N
Example 16
N- [4- [4- (6-Fluorobenzo [b] thien-3-yl) -1-piperazinyl] butyl] -2-hydroxy-2-methylpropanamide (Z) -2-butenedioate (1: 1)
To a solution of 2-hydroxyisobutyric acid (1.30 g, 12.5 mmol), pyridine (2.20 ml, 27.2 mmol), DMAP (190 mg, 1.56 mmol) and dichloromethane (60 ml) at ambient temperature Chlortrimethylsilane (3.40 ml, 26.8 mmol) was added dropwise over 3 minutes in a nitrogen atmosphere. After 4 hours, the reaction mixture was cooled to 0 ^° C. and a catalytic amount of DMF (2 drops from a Pasteur pipette) was added, followed by dropwise addition of oxalyl chloride (1.20 ml, 13.7 mmol). The reaction mixture was stirred at 0 ^o C and then 1 hour at room temperature for 30 minutes. The reaction mixture is cooled to 0 ^° C. and a solution of 4- (6-fluorobenzo [b] thien-3-yl) -1-piperazine-butanamine (3.50 g, 11.4 mmol), pyridine (3, 30 ml, 40.8 mmol) and dichloromethane (40 ml). After 35 minutes at 0 ^° C., the reaction mixture was stirred at room temperature for 18 hours. A solution of citric acid (4.60 g, 23.9 mmol) and methanol (50 ml) was added and the reaction mixture was stirred at room temperature for 50 minutes. After removing the solvent in vacuo, the residue was dissolved in dichloromethane (125 ml), washed successively with 5% aqueous NaOH (100 ml) and water (100 ml), dried (K ₂ CO ₃ ). The solvent was removed in vacuo and the resulting brown liquid was chromatographed on silica gel with 5% methanol in dichloromethane as an eluent to give 2.36 g of a gum.

The free base (2.10 g, 5.34 mmol) was dissolved in ethanol (50 ml), filtered and maleic acid (650 mg, 5.60 mmol) was added to the filtrate. The resulting mixture was heated until a solution was obtained and the solvent was removed in vacuo to give an orange solid. The salt was recrystallized again from methanol / ethyl acetate to give 1.18 g (20%) of the title compound as off-white plates. Mp 153-155 ^o C.

Analysis:
Calculated for C ₂₀ H ₂₈ FN ₃ S • C ₄ H ₄ O ₄ : 56.57% C 6.33% H 8.25% N
Found: 56.12% C 6.30% H 8.20% N
Example 17
N- [4- [4- (6-Fluorobenzo [b] thien-3-yl) -1-piperazinyl] butyl] - 4 '- (trifluoromethyl) - [1,1'-biphenyl] -2-carboxamide (Z ) -2-butenedioate (1: 1)
To a mixture of 4 '- (trifluoromethyl) - [1,1'-biphenyl] -2-carboxylic acid (2.60 g, 9.77 mmol), catalytic DMF and anhydrous dichloromethane (30 ml) at room temperature under nitrogen atmosphere was added oxalyl chloride (1.38 g, 10.9 mmol) dropwise in 15 minutes and the reaction mixture was stirred at room temperature. After 18 hours, the yellow reaction solution was concentrated in vacuo to give 2.51 g of 4 '- (trifluoromethyl) - [1,1'-biphenyl] -2-carbonyl chloride as a cloudy yellow liquid, which was used without further purification.

To a 0 ^o C solution of 4- (6-fluorobenzo [b] thien-3-yl) -1-piperazinbutanamine (2.50 g, 8.13 mmol), triethylamine (1.31 g, 12.9 mmol) and dichloromethane (75 ml) in a nitrogen atmosphere add a solution of 4 '- (trifluoromethyl) - [1,1-biphenyl] -2-carbonyl chloride (2.51 g, 8.82 mmol) and dichloromethane (25 ml) per serving. The reaction mixture was stirred at 0 ^° C. for 0.5 hours and then at room temperature for 21.5 hours. The reaction mixture was washed successively with 5% aqueous NaOH (75 ml) and water (75 ml), dried (K ₂ CO ₃ ) and concentrated in vacuo. The crude product is chromatographed on silica gel with 5% dichloromethane as the eluent to give 3.29 g of the product as a white foam.

Maleic acid (0.656 g, 5.65 mmol) was added to a solution of the free base (2.99 g, 5.38 mmol) in ethanol (50 ml), and the resulting solution was concentrated in vacuo. The salt was recrystallized from ethyl acetate to give 2.57 g (47%) of the title compound as a white powder, mp. 158-160 ^o C.

Analysis:
Calculated for C ₃₀ H ₂₉ F ₄ N ₃ O • C ₄ H ₄ O ₄ : 60.80% C 4.95% H 6.26% N
Found: 60.52% C 5.06% H 6.15% N
Example 18
N- [4- [4- (6-Fluorobenzo [b] thien-3-yl) -1-piperazinyl] butyl] benzo [b] thiophene-2-carboxamide (Z) -2-butenedioate (1: 1)
To a solution at 0 ^° C. of 4- (6-fluorobenzo [b] thien-3-yl) -1-piperazinbutanamine (2.50 g, 8.13 mmol), triethylamine (1.24 g, 12.2 mmol) and dry dichloromethane (100 ml) under nitrogen atmosphere was added dropwise benzo [b] thiophene-2-carbonyl chloride (1.76 g, 8.95 mmol) over 15 minutes. Stirring is continued at 0 ^° C. for 1.5 hours and 17.5 hours at room temperature. The reaction mixture was then washed sequentially with 5% aqueous NaOH (75 ml) and water (75 ml), dried (Na ₂ SO ₄ ) and concentrated with dichloromethane as an eluent, to give 3.34 g of a white product.

Maleic acid (800 g, 6.89 mmol) was added to a solution of the free base (3.08 g, 6.59 mmol) in boiling methanol (300 ml) and the resulting solution was concentrated in vacuo to give a white solid. The salt was recrystallized from methanol / ethyl acetate to give 3.07 g (64%) of the title compound as white crystals. Mp 133-135 ^o C.

Analysis:
Calculated for C ₂₅ H ₂₆ FN ₃ S ₂ • C ₄ H ₄ O ₄ : 59.67% C 5.18% H 7.20% N
Found: 59.60% C 5.13% H 7.24% N
It should be understood that this description and the examples given above are for illustration and not limitation, and that various modifications and changes can be made without departing from the scope of this description of the invention, as defined by the attached paragraphs.

Claims (14)

1. Substituted benzothienyl piperazines of the general formula I

in which X represents hydrogen or halogen;
Y is —CN or —NR ¹ R ² ,
where l is an integer 1 or 2;
m is an integer equal to 0, 1 or 2;
n denotes an integer equal to 2, 3 or 4, except when Y is CN, then n may also be 1;
R ¹ is hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkylcarbonyl, (C ₃ -C ₁₂ ) cycloalkylcarbonyl, hydroxy (C ₁ -C ₆ ) alkylcarbonyl, phenylcarbonyl, optionally substituted with halogen or trifluoromethylphenyl, thienylcarbonyl or benzothienylcarbonyl, or R ¹ and R ² together with the nitrogen atom to which they are attached form a cycle

where A is C = 0 or CH ₂ ;
B is C = 0, CHOH, CH ₂ or CH ₂ CH ₂ ;
Z is hydrogen,
and their pharmaceutically acceptable acid addition salts, provided that when X = H, n cannot be 4 and R ¹ , R ² cannot be both hydrogen. 2. The compounds of formula I according to claim 1, in which X - is halogen, Y is —CN or —NR ¹ R ² , where l is the integer 1, m is the integer 0 or 2, n is the integer 2, 3 or 4, R ¹ is hydrogen or (C ₁ -C ₆ ) alkylcarbonyl, R ² as defined in paragraph 1, or R ¹ and R ² together with the nitrogen to which they are attached form a cycle

where A and B are as defined in claim 1, their pharmaceutically acceptable acid addition salts. 3. The compound according to claim 1 or 2, where X is halogen, Y is NR ¹ R ² , 1 is an integer of 1, m is 0 or 2, n is 2, 3 or 4, R ¹ is hydrogen or (C ₁ -C ₆ ) alkylcarbonyl, and R ² is hydrogen, (C ₁ -C ₁₀ ) alkylcarbonyl, (C ₃ -C ₁₂ ) cycloalkylcarbonyl, hydroxy (C ₁ -C ₆ ) alkylcarbonyl, thienylcarbonyl or benzothienylcarbonyl, and pharmaceutically acceptable acid addition salts .  4. The compounds of claims 1 to 3, wherein X is halogen, m is 0, and n is 4. 5. The compound according to claim 1 or 2, where X is 6-F, R ¹ is hydrogen or acetyl, and R ² is hydrogen, isopropylcarbonyl, adamantylcarbonyl, 4-fluorophenylcarbonyl, 2-thienylcarbonyl, 2-benzothienylcarbonyl, 2-hydroxy- 2-methyl-ethylcarbonyl or 2- [4- (trifluoromethyl) 1,1-biphenyl].  6. The compound according to any one of the preceding paragraphs, selected from 4- (6-fluorobenzo [b-] thien-3-yl) -1-piperazine butanamine (Z) -2-butenedioate, N- [4- [4- (6 -fluorobenzo [v] thien-3-yl) -1-piperazinyl] butyl acetamide, N-acetyl-N- [4- [4- (6-fluorobenzo [v] thien-3-yl) -1-piperazinyl] butyl] -2-methyl-propanamide, N- [4- [4- (6-fluorobenzo [v] thien-3-yl) -1-piperazinyl [butyl] -2-methyl-propanamide, N- [4- [ 4- (6-fluorobenzo [v] thien-3-yl) -1-piperazinyl] butyl] -4-fluorobenzamide, N- N- [4- [4- (6-fluorobenzo [v] thien-3-yl) -1-piperazinyl] butyl] -adamantane-1-carboxamide maleate, N- [4- [4- (6-fluorobenzo [v] thien-3-yl) -1-piperazinyl] butyl] -2-thiophenecarbox id (Z) -2-butenedioate, N- [4- [4- (6-fluorobenzo [v] thien-3-yl) -1-piperazinyl] butyl] -2-hydroxy-2-methyl-propanamide (Z) -2-butenedioate, N- [4- [4- (6-fluorobenzo [v] thien-3-yl) -1-piperazinyl] butyl] -4- (trifluoromethyl) - [1.1-biphenyl] -2-carboxamide ( Z) -2-butenedioate and N- [4- [4- (6-fluorobenzo [i] thien-3-yl) -1-piperazinyl] butyl] benzo [i] thiophen-2-carboxamide (Z) -2 butadiene. 7. The compound according to claim 1 or 2, where X is halogen Y - represents a group

I is equal to 1;
m is 0 or 2;
n is 2, 3 or 4;
A is C = O or CH ₂ , B is C = O, CHOH, CH ₂ or CH ₂ CH ₂ , and its pharmaceutically acceptable acid addition salts.  8. The compound of claim 7, wherein X is halogen, m is 0, and n is 4. 9. The compound according to claim 7 or 8, where X is 6-F, m is 0, n is 4, A is C = O or CH ₂ and B is C = O, CHOH or CH ₂ .  10. The compound according to any one of claims 1, 2, 7, 8 or 9, which is selected from N- [2- [4- (6-fluorobenzo [v] thien-3-yl) -1-piperazinyl] ethyl ] -phthalimide, 2- [2- [4- (6-fluorobenzo [v] thien-3-yl) -1-piperazinyl] ethyl] -2,3-dihydro-3-hydroxy-1H-isoindole-1- he, 2- [2- [4- (6-fluorobenzo [v] thien-3-yl) -1-piperazinyl] butyl] -1H-isoindole-1,3 (2H) -dione, 4- (6- fluorobenzo [v] thien-3-yl) -1- [4- (isoindol-2-yl) butyl] piperazine and 4- (6-fluorobenzo [v] thien-3-yl) -1- [4- ( isoindol-2-yl) butyl] piperazine (Z) -2-butenedioate.  11. The compound according to claim 1 or 2, which is 4- (6-fluorobenzo [v] thien-3-yl) -1-piperazine butanitrile (Z) -2-butenedioate.  12. The compounds of formula I according to any one of the preceding paragraphs, with antipsychotic activity.  13. An antipsychotic pharmaceutical composition, which includes a pharmaceutically acceptable carrier and an active ingredient, characterized in that the active ingredient contains a pharmaceutically effective amount of a compound according to any one of the preceding paragraphs. 14. The method of producing substituted benzothienyl piperazines of the general formula I according to claim 1, wherein X, l, m, n are as defined in claim 1, Y denotes a group NR ¹ R ² , where R ¹ and R ² together with a nitrogen atom, with which they are connected, form a cycle

where A, B and Z have the meanings indicated in claim 1, characterized in that the compounds of formula II are reacted

where X, Z and the integers l, m and n are as defined in claim 1,
reacted with a suitable reducing agent in an organic solvent to form a compound of formula III

or compounds of formula IV

and optionally reducing a compound of formula IV to form a compound of formula V

15. The method of producing substituted benzothienylpiperazines of the general formula I according to claim 1, wherein X, l, m, n are as defined in claim 1, Y is a group NR ¹ R ² , where R ¹ is hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkylcarbonyl, R ² is hydrogen, (C ₁ -C ₁₀ ) alkylcarbonyl, (C ₃ -C ₁₂ ) cycloalkylcarbonyl, hydroxy (C ₁ -C ₆ ) alkylcarbonyl, phenylcarbonyl optionally substituted with halogen or trifluoromethylphenyl, thienylcarbonyl or benzothienylcarbonyl, characterized in that the compounds of formula II, as defined in clause 14, are reacted with sodium borohydride and vinegar oh acid in a suitable solvent to form a compound of formula VII

and optionally, a compound of formula VII is reacted with an organic acid chloride to form compound VIII

where R ^{2 is} defined in claim 1.

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